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Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies
Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradica...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467567/ https://www.ncbi.nlm.nih.gov/pubmed/34576300 http://dx.doi.org/10.3390/ijms221810137 |
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author | Salillas, Sandra Galano-Frutos, Juan José Mahía, Alejandro Maity, Ritwik Conde-Giménez, María Anoz-Carbonell, Ernesto Berlamont, Helena Velazquez-Campoy, Adrian Touati, Eliette Mamat, Uwe Schaible, Ulrich E. Gálvez, José A. Díaz-de-Villegas, María D. Haesebrouck, Freddy Aínsa, José A. Sancho, Javier |
author_facet | Salillas, Sandra Galano-Frutos, Juan José Mahía, Alejandro Maity, Ritwik Conde-Giménez, María Anoz-Carbonell, Ernesto Berlamont, Helena Velazquez-Campoy, Adrian Touati, Eliette Mamat, Uwe Schaible, Ulrich E. Gálvez, José A. Díaz-de-Villegas, María D. Haesebrouck, Freddy Aínsa, José A. Sancho, Javier |
author_sort | Salillas, Sandra |
collection | PubMed |
description | Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by narrow-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens. |
format | Online Article Text |
id | pubmed-8467567 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84675672021-09-27 Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies Salillas, Sandra Galano-Frutos, Juan José Mahía, Alejandro Maity, Ritwik Conde-Giménez, María Anoz-Carbonell, Ernesto Berlamont, Helena Velazquez-Campoy, Adrian Touati, Eliette Mamat, Uwe Schaible, Ulrich E. Gálvez, José A. Díaz-de-Villegas, María D. Haesebrouck, Freddy Aínsa, José A. Sancho, Javier Int J Mol Sci Article Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by narrow-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens. MDPI 2021-09-20 /pmc/articles/PMC8467567/ /pubmed/34576300 http://dx.doi.org/10.3390/ijms221810137 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Salillas, Sandra Galano-Frutos, Juan José Mahía, Alejandro Maity, Ritwik Conde-Giménez, María Anoz-Carbonell, Ernesto Berlamont, Helena Velazquez-Campoy, Adrian Touati, Eliette Mamat, Uwe Schaible, Ulrich E. Gálvez, José A. Díaz-de-Villegas, María D. Haesebrouck, Freddy Aínsa, José A. Sancho, Javier Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies |
title | Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies |
title_full | Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies |
title_fullStr | Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies |
title_full_unstemmed | Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies |
title_short | Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies |
title_sort | selective targeting of human and animal pathogens of the helicobacter genus by flavodoxin inhibitors: efficacy, synergy, resistance and mechanistic studies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467567/ https://www.ncbi.nlm.nih.gov/pubmed/34576300 http://dx.doi.org/10.3390/ijms221810137 |
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